Project Summary Dr. Andrew Y. Koh is an Associate Professor in the Department of Pediatrics (Division of Hematology/Oncology) and Microbiology at the University of Texas Southwestern Medical Center and Director of Pediatric Hematopoietic Stem Cell Transplantation at Children?s Medical Center Dallas. Clinically trained in both Infectious Diseases and Hematology/Oncology and scientifically trained in microbiology and immunology. Dr. Koh has established a successful and independent research program focused on understanding how the gut microbiome modulates host immune responses in cancer and stem cell transplant (SCT) patients. His experiences as an active clinical oncologist and infectious diseases specialist, a basic/translational researcher, and mentor have positioned him to be an ideal candidate for the K24 Mentoring Career Development Award. For this project, he is particularly interested in using ?reverse translational? approaches to identify unique gut microbiome signatures associated with a particular disease phenotype in patients and then confirming causality in the laboratory using preclinical and in vitro models. Hence, his research program is well-poised to further dissect and elucidate the mechanisms by which specific gut microbiota modulate disease phenotypes in cancer and SCT patients with the ultimate goal of devising novel therapies to modulate the gut microbiota and promote patient health. This work has been supported by funding from the NIH/NIAID (K08 and R01), the Centers for Disease Control and Prevention, private foundations, and industry. He has also developed a significant professional interest in mentoring trainees in translational microbiome research and career development. The K24 award will support Dr. Koh?s scientific career activities by allowing him to engage in professional development via coursework/training and execution of novel projects that will enhance his research program and support future independent funding. In addition to supporting scientific career activities, the K24 award will directly allow Dr. Koh to pursue mentorship/leadership training and enhance his ability to more deeply engage with specific mentees pursuing K and R01 awards and more broadly engage with all mentees in patient-oriented microbiome research. The overall scientific aims of this proposal are 1) To mentor trainees to become patient-oriented research investigators; 2) To continue and enhance my career development as a leader in translational patient- oriented research; and 3) To conduct independent translational microbiome research to improve the health of cancer and SCT patients with a focus on the following specific research projects: a) Mechanisms of gut colonization resistance to bacterial and fungal pathogens, with a translational focus on devising novel methods to precisely edit the microbiome and prevent invasive bacterial/fungal infections; b) Gut microbiota-dependent modulation of graft-versus-host disease; c) Mechanisms by which gut microbiota augment host anti-tumor response in the context of cancer immunotherapy; and d) Host and microbial determinants of microbial antibiotic resistance.